[Stopping antidepressants: withdrawal symptoms and rebound effects : Review and practical recommendations]. / Absetzen von Antidepressiva ­ Absetzsymptome und Rebound-Effekte : Übersicht und praktische Empfehlungen.

Stopping antidepressants can cause withdrawal (discontinuation) symptoms, the return of the original illness, and rebound. The latter means that the disease will return stronger, faster, or with greater likelihood than if it had not been treated with medication. The Psychiatry Working Group of the Drug Commission of the German Medical Association (AkdÄ) presents the scientific findings and provides practical recommendations for action. Withdrawal symptoms are multiform; unspecific physical symptoms are predominant. Distinguishing them from the recurrence of depressive symptoms can be difficult. Most of them are mild and self-limiting. There is insufficient evidence on the extent and frequency of rebound depression. The rebound risk implies that when establishing the medication, the short-term benefit must be weighed against the possible long-term risk of chronic depression or the possible need for long-term medication. Patients should be informed about the risk of withdrawal both as early as the joint decision-making process about treatment initiation and regularly during the course of treatment. Withdrawal should take place gradually, except in emergency situations, whereby small steps should be taken, especially in the low-dose range.

Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

[Genetic tests for controlling treatment with antidepressants]. / Genetische Tests zur Steuerung der Behandlung mit Antidepressiva.

In clinical practice, there is a need for a more individualized selection of antidepressants and adequate dosage. The investigation of pharmacokinetically relevant genes is a promising approach to assist this selection. In the past 2 years, two commercially available tests have been subject of advertisement, a test from Stada, which analyses variants of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 and a test from HMNC Brain Health, which analyses variants of the ABCB1 gene. The costs for both kits are not covered by the statutory health insurance and it is therefore proposed that the patients are invoiced directly in the form of individual healthcare payment. The companies claim that by applying the tests antidepressant treatment failure can be avoided and that patients will respond faster to the antidepressant used. These claims are not based on appropriate clinical trials, which are either lacking or reveal conflicting results. Hence, the routine use of these tests is not recommended. In accordance with the German S3 Guideline for unipolar depression, therapeutic drug monitoring (TDM) of serum levels should be carried out in cases of non-response to an antidepressant with adequate dosage and duration. As a rule the costs for TDM are covered by the statutory health insurance. Cytochrome P450 genotyping is only indicated when the serum level is not within the expected range and other reasons to explain this discrepancy are excluded. Many laboratories provide these analyses and in individual cases the costs are reimbursed by the statutory health insurance. Further research should be carried out to investigate the importance of the ABCB1 gene for the treatment with antidepressants.

[Psychopharmaceuticals for treatment of suicidal patients and for suicide prevention]. / Psychopharmaka zur Behandlung suizidaler Patienten und zur Suizidprävention.

Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term "suicidality" seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided.

[New facts of long-term prophylaxis for bipolar affective disorder]. / Neue Fakten zur Phasenprophylaxe der bipolar affektiven Erkrankung.

Lithium and with restrictions, carbamazepine, valproic acid, lamotrigine, olanzapine, aripiprazole and quetiapine, are approved in Germany for maintenance treatment of bipolar disorder. Lithium is the only drug that (I) proved to be effective for the prevention of depressive as well as manic episodes in state-of-the-art studies without an enriched design and that (II) is approved for the maintenance treatment of bipolar disorders without restrictions. It (III) is also the only drug which is recommended for maintenance treatment by the current German S3 guidelines on bipolar disorders with the highest degree of recommendation (A) and (IV) is the only drug with a well proven suicide preventive effect. Hence, lithium is the mood stabilizer of first choice. No patient should be deprived of lithium without a specific reason. Side effects and risks are manageable if both the physician and the patient are well informed. Detailed and practical information on a safe use of lithium can be found in the S3 guidelines on bipolar disorders. For patients who do not respond sufficiently to lithium, have contraindications or non-tolerable side effects, other mood stabilizers should be used. Restrictions in their respective approval as well as specific side effects and risks have to be taken into account. Because maintenance treatment is a long-term treatment, particular concern should be paid to drugs with the potential risk of a metabolic syndrome, particularly atypical antipsychotics.

[Anti-suicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders]. / Suizidprophylaktische Wirkung von Lithium : Aktueller Forschungsstand und Implikationen für die Therapie affektiver Störungen.

Treatment of patients with suicidal behaviour is one of the most challenging tasks for health care professionals. Due to the high mortality, morbidity and costs related to suicide, the development of treatment and preventive strategies for suicidal behaviour have been a focus of psychiatric research. For lithium, one of the oldest pharmacological agents used in psychiatry, anti-suicidal effects have been found since the early 90s in many international studies. Despite this unambiguous evidence and corresponding recommendations in national and international guidelines for the acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a review of studies investigating the anti-suicidal effects of lithium in affective disorders. Clinical implications for the treatment of affective disorders are discussed.

[Antipsychotics for treatment of neuropsychiatric disorders in dementia]. / Antipsychotika zur Behandlung neuropsychiatrischer Störungen bei Demenz.

Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.

[Antidepressants for treatment of depression in palliative patients : a systematic literature review]. / Antidepressiva zur behandlung der depression bei palliativpatienten : eine systematische literaturübersicht.

BACKGROUND: Treatment of depression in palliative care must take into account expected benefits and risks of antidepressants in patients with potentially limited life expectancy, poor medical condition, advanced age and higher risk to suffer from side effects and drug interactions. This systematic review assesses evidence of the efficacy and safety of different classes of antidepressants depending on the type and severity of the physical illness. METHODS: A systematic database search (Medline, EMBASE) for clinical studies was carried out and references of identified literature were checked. To be included in the review studies had to be performed in illnesses that were part of in the search strategy, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, HIV/AIDS, cancer, COPD and heart failure. Considered were controlled studies comparing the efficacy of antidepressants to placebo, other classes of antidepressants, benzodiazepines, psychostimulants or psychotherapy. In a first step only studies with patients meeting established diagnostic criteria of depression and where depression was a primary endpoint were included. In a second step, additional studies were included that did not meet both of the latter criteria but were performed in patients at the end of life. RESULTS: A total of 40 trials (mostly using SSRI or NSMRI) were included, 16 studies were performed in neurological, 24 in general medical conditions and 9 studies were performed in patients at the end of life or in advanced disease stages. Due to heterogeneous study designs no conclusions can be drawn if efficacy or tolerability is dependent on disease severity. In most cases, studies might have been too small to detect limited treatment effects. As a lack of efficacy was predominantly shown in larger trials, publication bias might have been present. In most of the reviewed general medical conditions study results were heterogeneous. In contrast to the popularity of the treatment approach, results suggest that SSRIs are not effective in Alzheimer's disease. In Parkinson's disease, negative studies are too small to prove lack of efficacy of SSRIs as present in the majority of trials. CONCLUSIONS: This review of the evidence allows only limited conclusions concerning the use of antidepressants in physical illness disorders at the end of life. The reviewed evidence does not allow direct conclusions to be drawn concerning the use of antidepressants in different disease severities and its benefits compared to other treatment options (psychotherapy, benzodiazepines etc.). The English full text version of this article will be available in SpringerLink as of November 2012 (under "Supplemental").

Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial.

OBJECTIVE: Evidence based on controlled studies is still limited for treatment strategies that prevent recurrence of suicide attempts. Findings from observational as well as meta-analytic studies strongly suggest that lithium may have suicide-protective properties. METHOD: Patients with a recent suicide attempt in the context of an affective spectrum disorder (n = 167) were treated with either lithium or placebo during a 12-month period. RESULTS: Survival analysis showed no significant difference of suicidal acts between lithium and placebo-treated individuals (adjusted hazard ratio 0.517; 95% CI 0.18-1.43). However, post hoc analysis revealed that all completed suicides had occurred in the placebo group accounting for a significant difference in incidence rates (P = 0.049). CONCLUSION: Results indicate that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with affective disorders. Our findings contribute to the growing body of evidence suggesting a specific antisuicidal effect of lithium.

Is MAO-B activity in platelets associated with the occurrence of suicidality and behavioural personality traits in depressed patients?

OBJECTIVE: Low platelet monoaminoxidase B (MAO-B) activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls. METHOD: In 87 patients with affective spectrum disorders (58% suffering from a major depressive episode - MDE) the potential association between platelet MAO-B activity and suicidality was examined. Fifty-nine of the patients had committed suicide attempt recently (SA -'suicide attempters'), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA -'non-suicide attempters'). RESULTS: The SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the SA was observed. CONCLUSION: Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated.

The suicide prevention effect of lithium: more than 20 years of evidence-a narrative review.

The management and treatment of patients with suicidal behavior is one of the most challenging tasks for health-care professionals. Patients with affective disorders are at high risk for suicidal behavior, therefore, should be a target for prevention. Numerous international studies of lithium use have documented anti-suicidal effects since the 1970s. Despite the unambiguous evidence of lithium's anti-suicidal effects and recommendations in national and international guidelines for its use in acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a comprehensive review of studies investigating the anti-suicidal effect of lithium in patients with affective disorders.

Sensation seeking and auditory evoked potentials.

The relationship between auditory evoked potentials (AEP) and the German version of Zuckerman's Sensation Seeking Scale was examined. The slope of the amplitude/stimulus intensity function (N1/P2 component) and the N1 latency were particularly studied, as these variables have been found to be potential predictors of the response to lithium prophylaxis. Thirty-three healthy subjects participated in two testing series on the first day and in a third run 3 weeks later. Binaural clicks at four intensity levels (58, 68, 78, 88 dB HL, ISI 2.1 sec) were presented in randomized order by headphone. Eighty responses were averaged at each intensity level. The pattern of correlation between the German version of the Sensation Seeking Scale and a personality inventory (FPI) supports the validity of the Sensation Seeking Scale. Only a tendency toward steeper slopes of the amplitude/stimulus intensity function (ASF) in high sensation seekers was observed in the first run. However, there was a significant interaction of sensation seeking and the test run. Only high sensation seekers showed an influence of retesting on the slope of the ASF, leading to a decrease of the slope in the second, compared with the first run. This might correspond to the psychological pattern of sensation seeking, which is characterized by a permanent need for new and exciting situations and, at the same time, by a rapid loss of interest in these situations. With regard to the N1 latency, a significant interaction of sensation seeking and lead was found. Low sensation seekers showed longer N1 latencies over the right than over the left hemisphere, a finding that accords with some psychophysiological theories on the relation between asymmetric hemispherical activation and certain psychological constructs. Our results support the view that sensation seeking is a personality feature that is closely related to certain physiological variables.

Phototherapy in nonseasonal depression.

Previous reports have shown that bright light exposure may benefit patients with seasonal depression. In the present study, the possible therapeutic effect of bright light in nonseasonal major depressive disorder was examined. Forty-two depressed patients not receiving additional antidepressant medication were exposed to bright white light of 2500 lux or dim red light of 50 lux over one week for two hr daily in the morning. The change in depressive symptoms was assessed by rating scales (Hamilton Depression Rating Scale, CGI) and by self-rating scales (Depression Scale, Complaint List, Visual Analogue Scale). Consistent for all ratings, the decrease in depressive symptoms after bright white light was only slight and not different from dim red-light exposure. Contrary to the findings in seasonal affective disorder, phototherapy administered over one week for two hr daily is not effective in nonseasonal major depressive disorder.

Lithium effect on smooth pursuit eye movements of healthy volunteers.

Smooth pursuit eye movement (SPEM) dysfunctions in major affective disorder patients have been reported to be associated with lithium treatment. We report that SPEM of 13 healthy volunteers, either taking lithium (n = 7) or placebo (n = 6), were not significantly impaired by lithium. This could point to a pathophysiologic difference between affective disorder patients and a normal population.

Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism.

AIM: The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N-oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine. METHODS: This study included 204 patients treated with clozapine for schizophrenia and 192 healthy volunteers receiving a 100 mg oral test dose of caffeine. FMO3 polymorphisms M66I, P153L, E158K, V257M, E305X, E308G, and R492W were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity. RESULTS: From the known FMO3 amino acid variants, only K158 (frequency 0.426), G308 (0.225), and M257 (0.069) were found; mutations I66, L153, X305, and W492 were not found in the 396 subjects. Linkage analysis revealed seven different alleles; the most frequent of these was the wild-type E158-V257-E308 (0.534), followed by K158-V257-G308 (0.199) and K158-V257-E308 (0.192). Subjects with these frequent variants of FMO3, however, did not differ in clozapine N-oxidation or caffeine oxidation compared with the wild-type. CONCLUSION: There are several genetic polymorphisms for the FMO3 enzyme. The effects on the metabolism of caffeine or clozapine could not be shown, indicating that the mutations have only minor functional effects or that substrate affinity is too low to be clinically relevant.

Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression.

OBJECTIVE: Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression. The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder. METHOD: Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a randomized, parallel-group, double-blind, placebo-controlled trial of lithium augmentation during continuation treatment. After a 2-4-week stabilization period following remission, patients were randomly assigned to receive either lithium or placebo for a 4-month period. Antidepressant medication was continued throughout the study. RESULTS: Relapses (including one suicide) occurred in seven (47%) of the 15 patients who received placebo in addition to antidepressants. None (0%) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study. Five of the seven relapsing patients in the placebo group developed a depressive episode, and the other two experienced a manic episode. CONCLUSIONS: Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse. Patients who respond to lithium augmentation should be maintained on lithium augmentation for a minimum of 6 months or even longer.